nih public access medicinally-relevant products curr top ......fluorinated organic compounds have a...

Decarboxylative Fluorination Strategies for AccessingMedicinally-relevant Products

Yupu Qiao, Lingui Zhu, Brett R. Ambler, and Ryan A. AltmanDepartment of Medicinal Chemistry, the University of Kansas, 1251 Wescoe Hall Dr., 4046AMalott Hall, Lawrence, KS 66049, USA

Ryan A. Altman: [email protected]

Abstract

Fluorinated organic compounds have a long history in medicinal chemistry, and synthetic methods

to access target fluorinated compounds are undergoing a revolution. One powerful strategy for the

installation of fluorine-containing functional groups includes decarboxylative reactions. Benefits

of decarboxylative approaches potentially include: 1) readily available substrates or reagents 2)

mild reaction conditions; 3) simplified purification. This focus review highlights the applications

of decarboxylation strategies for fluorination reactions to access compounds with biomedical

potential. The manuscript highlights on two general strategies, fluorination by decarboxylative

reagents and by decarboxylation of substrates. Where relevant, examples of medicinally useful

compounds that can be accessed using these strategies are highlighted.

Keywords

decarboxylation; fluorination; difluoromethylation; trifluoromethylation; copper

1) Introduction

Synthetic methods for the efficient incorporation of fluorinated functional groups enable the

rapid construction of biologically interesting molecules and therefore, are important for

medicinal chemistry [1–2]. Although many creative and elegant fluorination strategies have

recently been developed [3–6], a need remains for new transformations that grant access to

unique products and that rely on principles of green chemistry [7]. One emerging approach

that has gained appreciation in non-fluorine chemistry involves decarboxylative coupling

[8–9]. This strategy typically exhibits several appealing features, including the: 1) use of

inexpensive and readily accessible starting materials; 2) ability to selectively generate

reactive species under mild reaction conditions; 3) release of CO2 as a benign and easily

removed by-product [9]. Given these benefits, decarboxylative coupling represents an

attractive approach for the installation of fluorine and fluorinated functional groups into

organic compounds. The following manuscript discusses historical strategies for

Correspondence to: Ryan A. Altman, [email protected].

CONFLICT OF INTERESTThe author(s) confirm that this article content has no conflicts of interest.

NIH Public AccessAuthor ManuscriptCurr Top Med Chem. Author manuscript; available in PMC 2015 January 01.

Published in final edited form as:Curr Top Med Chem. 2014 ; 14(7): 966–978.

NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

decarboxylative fluorination to provide a framework for presenting recent developments in

the field. The discussion is divided into two general sections: 1) decarboxylation of reagents

to generate reactive fluorinated species; 2) decarboxylation of substrates to generate reactive

species that can be converted to fluorinated functional groups. Within these two topics, only

reactions that utilize decarboxylation to form new C–F or C–C(F)n bonds are considered.

2) Fluorination by Decarboxylative Reagents

2.1 Introduction to Reagents

The development of reactions that utilize inexpensive, atom-economical reagents represents

a goal of green chemistry [7]. Halodifluoroacetic acids represent an attractive class of

reagents that undergo decarboxylation to release reactive fluorinated species. While

trifluoroacetic acid is the least expensive and most desirable reagent in this class, it

decarboxylates slowly, and has an estimated half-life of 40,000 years at 15 °C in aqueous

solution [10]. Trifluoroacetates have found synthetic utility as fluorinating reagents and will

be discussed later in this section; however, decarboxylation typically requires stoichiometric

Cu and reaction temperatures >150 °C [11–13]. Other halodifluoroacetic acids

decarboxylate more rapidly (Fig. 1); however, metal catalysts, other reagents, and/or high

temperatures are required to facilitate synthetically useful transformations.

In contrast, halodifluoroacetates decarboxylate to generate both :CF2, and in the presence of

F−, −CF3, which can be utilized in a variety of synthetic transformations. The reactivity

trend of halodifluoroacetic acids is consistent for both catalyzed and non-catalyzed

conditions. Bromo-and chlorodifluoroacetates decarboxylate at lower temperatures (50–130

°C), and therefore, are more commonly employed than trifluoroacetates. These milder

conditions allow for increased functional group compatibility, which in turn enables the

installation of fluorinated groups into a broader array of molecules.

The present section focuses on reactions involving the use of halodifluoroacetates as sources

of :CF2 and −CF3, and concludes with discussion of other decarboxylative fluorination

reagents closely related to halodifluoroacetates.

2.2 Decarboxylative Trifluoromethylation of Halodifluoroacetate Esters

Activated alcohols have been converted to trifluoromethanes via a two-step procedure

involving formation of a halodifluoroacetic ester followed by reaction with stoichiometric

CuI in the presence of fluoride (Fig. 2) [14]. Substrates were limited to simple primary

allylic, benzylic, and propargylic alcohols. Allylic and benzylic halodifluoroacetates

underwent formal SN2 substitution, while propargylic chlorodifluoroacetates underwent

formal SN2′ substitution to yield trifluoromethylallenes [14]. Bromodifluoroacetic esters

displayed greater reactivity than chlorodifluoroacetic esters, and produced higher yields (ca.

10%) at 20–30 °C lower reaction temperatures [14]. Most commonly, a two-step procedure

was employed in which an activated alcohol was converted to a halodifluoroacetate,

purified, and then subjected to stoichiometric CuI and KF. A two-step, one-pot procedure

was also developed that utilized ethyl halodifluoroacetates and afforded the product in

moderate to low yield [14].

Qiao et al.

Curr Top Med Chem. Author manuscript; available in PMC 2015 January 01.

NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

The mechanism of Cu-mediated decarboxylative trifluoromethylation was proposed to

proceed by a multi-step process that involves both CuI and the I− counterion (Fig. 3) [14].

Initially, the halodifluoroacetic ester reacted with CuI to yield an organic iodide and

CuO2CCF2X (Fig. 3A). Next, CuO2CCF2X decarboxylated to generate CuX, CO2, and :CF2

(Fig. 3B). In the presence of KF, an equilibrium was established that formed −CF3 (Fig. 3C).

CuI subsequently reacted with −CF3 to form Cu–CF3 (Fig. 3D). Finally, Cu–CF3 reacted

with the organic iodide to yield the trifluoromethyl product (Fig. 3E). Product was not

formed in the absence of either CuI or KF [14].

This procedure has been employed to access an allylic trifluoromethyl building block, as a

precursor to biologically relevant molecules. In one example, a one-pot, two-step conversion

of an allylic alcohol to an allylic trifluoromethane was employed for the synthesis of the

COX-2 inhibitor, L-784,512 (Fig. 4) [15]. Initial treatment of alcohol 1 with

chlorodifluoroacetic anhydride in the presence of N,N-diisopropylethylamine (DIPEA)

yielded intermediate ester 2. Addition of KF and stoichiometric CuI and heating at 90 °C for

1 h, provided the product trifluoromethane 3 in high yield. Interestingly, DIPEA was critical

for the reaction, as the use of NEt3, pyridine, or K2CO3 resulted in formation of the

corresponding allylic chloride, and 30–60% lower yield of desired product. The one-pot

procedure was more efficient than a two-step procedure in which alcohol 1 was first

converted to an allylic iodide, and subsequently treated with CuI and MeO2CCF2Cl.

Subjection of trifluoromethane 3 to Sharpless asymmetric dihydroxylation, alcohol

oxidation, and coupling/cyclization reactions afforded L-784,512 [15].

Recent research has focused on the development of more green reaction sequences that

utilize catalytic quantities of Cu. Towards this end, the decarboxylative trifluoromethylation

of primary allylic bromodifluoroacetates was conducted in the presence of catalytic CuI

(Fig. 5) [16]. A variety of functional groups were tolerated, including aryl halides, N- and O-

containing functional groups, and a variety of substitution patterns on the alkene. The

system benefited from the use of N,N’-dimethylethylenediamine (DMEDA) as a ligand, and

a catalyst activation procedure in which a solution of CuI, DMEDA, and NaO2CCF2Br were

heated before the addition of substrate. The procedure presumably generated a DMEDA–

Cu–CF3 species that facilitated entry into the catalytic cycle (Fig. 5). The Cu–CF3 species

generated during activation presumably underwent substitution with allylic

bromodifluoroacetate, resulting in the formation of product and DMEDA–Cu–O2CCF2Br.

Decarboxylation and formal halogen exchange allowed catalyst turnover and regeneration of

a DMEDA–Cu–CF3 species. Unlike the proposed mechanism for the Cu-mediated allylic

trifluoromethylation, the mechanism of the Cu-catalyzed reaction did not invoke an allylic

iodide intermediate; control reactions provided comparable yields in the presence and

absence of iodide. For substrates containing Z-alkenes, isomerization to more stable E-

alkene products was observed (Fig. 5). Therefore, this allylic substitution might proceed via

a π–allyl intermediate, which has been invoked to explain substitution reactions of allylic

halides and trifluoroacetates from well defined (PPh3)3Cu–CF3 complexes [17] and Cu–CF3

complexes generated in situ [18].

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

2.3 Aromatic Trifluoromethylation

A series of trifluoromethylating reagents, including halodifluoroacetate salts and esters, and

fluorosulfonyldifluoroacetate salts and esters were developed [19–27], and have been

applied to the trifluoromethylation of aryl and heteroaryl halides (Fig. 6) [19–30]. Generally,

these reagents undergo Cu-mediated decarboxylation of the reagent in situ to release :CF2,

and then react with F− to generate −CF3. Most of these reagents are commercially available,

and those that are not, such as KO2CCF2SO2F, are easily accessible [26]. Historically, aryl

trifluoromethylation reactions with these reagents required high temperatures, stoichiometric

CuI, and polar solvents such as N,N-dimethylformamide (DMF) or N,N-dimethylacetamide

(DMAc). For these reactions, reactivity trends of aryl and heteroaryl halides mimic trends of

other Cu-based coupling reactions (Ar–I > Ar–Br ≫ Ar–Cl) [31]. The introduction of

electron-withdrawing groups, such as NO2, to the aromatic ring can improve the reactivity

of aryl halides, especially aryl chlorides.

Traditionally, decarboxylative aromatic trifluoromethylation required stoichiometric CuI;

however recently, reactions utilizing catalytic CuI were reported [29–30]. In one example,

the Weinreb amide derived from a 5-bromo-2-iodobenzoic acid underwent

trifluoromethylation in the presence of MeO2CCF2SO2F and catalytic CuBr (Fig. 7) [29]. In

this unique example, the amide may have served as a directing group to help facilitate the

reaction. For substrates lacking directing groups, Cu-catalyzed reactions have been achieved

through the use of 1,10-phenanthroline as a ligand (Fig. 7) [30]. Unfortunately, when this

Cu-catalyzed reaction was conducted on a multi-kilogram scale, the formation and

separation of Ar(CF2)nCF3 side products proved problematic [30]. These byproducts

resulted from insertion of :CF2 into Cu–CF3, and were suppressed by reverting to the use of

stoichiometric CuI.

Fluorine-18-labelled organic molecules are used for positron emission tomography (PET)

[32]. Recently, a method of decarboxylative trifluoromethylation enabled the preparation of

Ar–CF3[18F] based PET imaging agents (Fig. 8) [32]. This procedure generated radiolabeled

Cu–[18F]CF3 in situ from MeO2CCF2Cl, CuI, N,N,N’,N’-tetramethylethylenediamine

(TMEDA), and [18F]KF/kryptofix. Under the reaction conditions, a diverse set of aryl and

heteroaryl iodides were rapidly trifluoromethylated. While some medicinally important

functional groups, such as acids and amines, were not compatible with the reaction

conditions, an example of a successful protection strategy was demonstrated by synthesis of

[18F]fluoxetine (selective serotonin reuptake inhibitor) (Fig. 8). Due to the large scope of

substrates and operational simplicity, this transformation should facilitate the drug discovery

process. For more details on PET imaging agents, the reader is referred to an alternate article

[33].

Compared to halodifluoroacetates, trifluoroacetic acid derivatives represent more ideal

reagents for trifluoromethylation, because they are less expensive and do not require the

addition of fluoride to generate −CF3. To this end MeO2CCF3 has served as a

trifluoromethylating reagent in the presence of stoichiometric CuI and promoters, such as

CsF or CsCl [34]. The trifluoromethylation of aryl and heteroaryl halides (the reactivity: ArI

> ArBr ≫ ArCl) using MeO2CCF3 provided the corresponding benzotrifluorides in 42–79%

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

yield, using DMF at 180 °C or sulfolane at 140–180 °C. However, the use of stoichiometric

Cu limits the economic value of the transformation, and the development of a method that

employs only catalytic quantities of a Cu salt represents a desirable target. The CuI-

catalyzed decarboxylative trifluoromethylation of aryl and heteroaryl halides with

MeO2CCF3 using CsF as initiator provided products in 47–95% yield (Fig. 9). To achieve

the catalytic variant, MeO2CCF3 was added at a rate so that the slow decarboxylation step

(k1) matched the consumption of CuCF3 in the aromatic trifluoromethylation step (k2). For

some less active aryl bromides, the use of 1,10-phenanthroline as ligand proved helpful for

the trifluoromethylation reactions [35].

Alkali trifluoroacetate salts are also inexpensive and readily available, and represent

attractive sources of CF3 for large-scale processes. As early as 1981, the decarboxylative

trifluoromethylation of aryl iodides and bromides occurred using NaO2CCF3 in the presence

of CuI [36]. Further investigations confirmed the reactivity of a cuprate, [F3CCuI]−, with

aryl halides to deliver the trifluoromethylated products (Fig. 10A) [11]. Although the use of

the trifluoroacetate salts makes this a desirable protocol for trifluoromethylation, the use of

stoichiometric CuI and high reaction temperature to promote decarboxylation (160–180 °C)

limited the method to reactions of stable substrates. To address this problem, the use of

Ag2O as an additive (30–40 mol%) allowed the analogous CuI-catalyzed reaction of aryl

iodides to occur using NaO2CCF3 at reduced temperature (130 °C) [37]. For this reaction,

the Ag2O was essential, and might lower the activation energy of decarboxylation of sodium

trifluoroacetate to generate AgCF3 in situ (Fig. 10B).

Another commercially available trifluoroacetate salt, KO2CCF3, can also be used in the

trifluoromethylation of aryl and heteroaryl halides. The CuI-mediated trifluoromethylation

of a bromotetrahydronaphthalene with KO2CCF3 afforded the product in 35% yield [38],

and the CuI-mediated trifluoromethylation of N-protected 5-bromoisoindoline with

KO2CCF3, using toluene as co-solvent, provided the desired product in 90% yield [39].

However, the reaction time of the latter was far less than the former (1.5 h vs. 2 d), which

may be attributed to the electron-withdrawing group at the meta-position of the bromide or

the coordinating ability of the –OMe group (Fig. 11).

Chemical reactions conducted in flow microreactors have several advantages over

traditional reaction vessels including: 1) precise control of reaction variables, such as

temperature and rates of mixing; 2) increased safety profiles; 3) the ability to perform

multiple transformations without isolating potentially reactive species [40]. Flow chemistry

has facilitated various fluorination reactions, and recently, enabled the rapid and efficient

trifluoromethylation of aryl and heteroaryl iodides using KO2CCF3 [41]. In the flow reactor,

a solution of KO2CCF3, CuI and pyridine in NMP was mixed with a solution of aryl or

heteroaryl iodides, and the mixture was introduced into a stainless steel tube reactor

submerged in a preheated 200 °C bath using an optimized 16 minutes residence time (Fig.

12). At this point, the mixture was diluted with a stream of ethyl acetate (controlled with a

back regulator), and the resulting mixture was collected and purified to afford

trifluoromethylated arenes in good to excellent yields [41].

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

In addition to the systems described above, trifluoromethylation of aryl halides has been

accomplished using well-defined NHC–Cu–O2CCF3 and –O2CCF2Cl complexes. Upon

heating, the complexes released CO2 and generated NHC–Cu–CF3, which reacted with aryl

electrophiles [42]. When aryl halide was used as the solvent, the ligated copper complex

provided trifluoromethylated products in higher yields than “ligandless” CuI. However,

when the aryl halide was used as only a co-solvent with DMAc, the copper complexes did

not perform superior to reaction of CuI with MO2CCF3 and MO2CCF2Cl (Fig. 13).

2.4 Difluoroolefination

Halodifluoroacetate salts can also serve as regents for difluoroolefination reactions (Fig. 14).

An early one-step synthesis of l,l-difluoroolefins involved heating a solution of an aldehyde,

PPh3 and NaO2CCF2Cl [43].

Three mechanisms were proposed for the conversion of carbonyl compounds to

difluoroolefins (Fig. 15) [44]. Mechanism A would involve the decomposition of

NaO2CCF2Cl to generate :CF2, which would then react with PPh3 to form a phosphonium

ylide. In the presence of a carbonyl compound, the phosphonium ylide could then react via a

Wittig mechanism to form product [43]. Mechanism B involved initial reaction of

NaO2CCF2Cl and PPh3 to generate Ph3P+CF2CO2−. This species would then decarboxylate

to form the common phosphonium ylide species. Finally, mechanism C would involve a

reaction between NaO2CCF2Cl and PPh3 to form an enolate and a phosphonium species,

which would decompose to form a phosphonium ylide.

In order to distinguish between these potential reaction pathways, a series of experiments

were conducted. First, NaO2CCF2Cl and PPh3 were heated in the presence of two :CF2-

trapping reagents, tetramethylethylene and isopropyl alcohol. Formation of

difluorocyclopropane was not observed, which suggested that free :CF2 was not present in

solution [45]. A second experiment monitored the evolution of CO2, when NaO2CCF2Cl

was heated in the presence and absence of PPh3 [45]. The decomposition of the salt was

accelerated in the presence of PPh3, and required only 4–6 h to evolve 70% of the theoretical

amount of CO2. In contrast, the decomposition of the salt in the absence of PPh3 was slow,

and required 17 h to achieve a comparable result. These data were able to discount

mechanism A; however, could not be used to differentiate mechanisms B and C.

The difluoroolefination reaction was later applied to various classes of ketones. For

activated ketones (Fig. 16A), good to excellent yields of difluoroalkenes were obtained

using the standard reaction conditions (PPh3, NaO2CCF2Cl, diglyme, 105 °C) [46];

however, non-activated substrates did not provide substantial quantities of products.

Replacement of PPh3 and diglyme with P(nBu)3 and N-methylpyrrolidone (NMP) (Fig. 16B)

allowed for the extension of the difluoromethylation reaction to some non-activated ketones

[47]; however in some cases, transfer of a butylidine group to the ketone formed a butylidine

side product [48]. Formation of this butylidene product occurred during the reaction with

various electrophilic substrates, including cyclohexanone, heptanal, and

trifluoroacetophenone. In the latter case, only the butylidene product was isolated from the

reaction mixture [48].

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

A rearrangement mechanism was proposed to explain the formation of butylidene product

(Fig. 17) [48]. However, further studies revealed that the butylidene product was directly

formed via reaction of P(nBu)3 and trifluoroacetophenone (Fig. 18) [49].

While earlier researchers favored mechanism B (Fig. 15) (formation of Ph P3P+CF2CO−2,

decarboxylation to provide Ph3P=CF2, then Wittig difluoromethylenation), they were unable

to isolate the key intermediate, Ph3P+CF2CO2−. Recently, the synthesis and characterization

of the key difluoromethylene phosphobetaine provided direct evidence for this reaction

mechanism [50]. To identify the proposed intermediate, PPh3 was reacted with KO2CCF2Br

instead of NaO2CCF2Cl, which allowed for the substitution reaction to proceed under mild

conditions, which allowed for the isolation of Ph3P+CF2CO2− in good yield (Fig. 19).

Ph3P+CF2CO2− was stable to storage in under ambient conditions, and provided a

convenient new reagent for the difluoromethylenation of aldehydes. Moreover, replacement

of PPh3 with P(NMe2)3 provided an alternate reagent, (Me2N)3P+CF2CO2− that reacted well

with non-activated ketones [50].

2.5 Cyclopropanation

Decarboxylative strategies have also been employed for the preparation of fluorinated

cyclopropanes. Early studies showed that thermolysis of NaO2CCF2Cl generated :CF2,

which reacted with cyclohexene to provide 60–65% of the theoretical amount of CO2 in

addition to 22% of difluoronorcarane (Fig. 20) [51].

Later, this strategy was applied to the difluorocyclopropanation of conjugated steroidal

dienes [52]. Both di- and tri-substituted alkenes reacted with :CF2 to provide a mixture of

isomeric adducts (Fig. 21). In addition, the conjugated double bond of an enone system was

also underwent difluorocyclopropanation [53]. However, high temperature 165–225 °C and

large amount of NaO2CCF2Cl (20–50 equiv) were required. Control studies showed that

cyclopropanation did not occur below 150 °C, even though decomposition of the salt

occurred at 125 °C.

This strategy was also applied for difluorocyclopropanation of other nonsteroidal alkenes,

including (Z)-4-(benzyloxy)-2-butenylacetate [54]. However, high temperature (190 °C) and

excesses NaO2CCF2Cl (11 equiv) were required to obtain reasonable yields. Subsequent

Zemplén deacetylation and Mitsunobu reactions allowed for the preparation of a large

number of nucleoside analogues as potential chemotherapeutic agents (Fig. 22A). This

strategy was also amenable to the stereospecific preparation of boron-substituted gem-

difluorocyclopropanes [55], which could be rapidly transformed to afford functionalized

gem-difluorocyclopropanes via lithium carbenoids or by subsequent oxidation (Fig. 22B).

Moreover, this strategy was used to synthesize cis- or trans-4,5-difluoromethanoproline

through difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline [56].

The two building blocks were stable and could be easily incorporated into the proline-rich

SAP peptide (Fig. 22C). Subsequently, a convenient synthesis of fluorinated cyclopropanes

and cyclopropenes was developed using NaO2CCF2Br as a source of :CF2 [57]. Compared

to NaO2CCF2Cl, NaO2CCF2Br was less hygroscopic at room temperature, and thus, easier

to handle. Further reactions using NaO2CCF2Br were more efficient, and tolerated the

presence of electron-deficient substrates (Fig. 22D).

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

The use of an alternative source of :CF2, trimethylsilyl fluorosulfonyldifluoroacetate

(TFDA), provided access to difluorocyclopropanes under more mild conditions [58] (Fig.

23A). In the presence of catalytic fluoride, TFDA easily decomposed to generate :CF2 (105

°C), and difluorocyclopropanes were obtained in high yields. The moisture-sensitive nature

of TFDA provided a poor shelf life, and made the reagent relatively challenging to handle.

Therefore, a more stable and convenient reagent was designed [59]. This new reagent,

MeO2CCF2SO2F, in combination with KI and TMSCl exhibited comparable reactivity as

TFDA at high concentration and high temperature [60]. Using MeO2CCF2SO2F, a broad

range of alkenes was converted into the corresponding difluorocyclopropanes, even

including unreactive n-butyl acrylate (Fig. 23B). To contrast the usage of MeO2CCF2SO2F

and TFDA, sodium trifluoroacetate can also serve as a precursor to :CF2 [61]. NaO2CCF3

decomposed at 170 °C in the presence of AIBN to form :CF2, which then reacted with a

variety of alkenes. Given the inexpensive nature of NaO2CCF3, this procedure provided an

economical method for difluorocyclopropanation of robust substrates.

Historically, little overlap existed between reactions that generate :CF2 and

difluoromethylene phosponium ylides. MO2CCF2X-based reagents decarboxylated to form

reactive :CF2 species that were used to generate difluorocyclopropanes. In contrast, regents

derived from MO2CCF2X and PPh3 generated difluoromethylene phosphonium ylides for

difluoroolefination reactions. However recently, the interconversion between

difluoromethylene ylide and :CF2 was successfully achieved [62]. By changing the solvent

from DMF to less-polar p-xylene, Ph3P+CF2CO2− was converted from a precursor of

difluoromethylene phosphonium ylide to an efficient precursor of :CF2 (Fig. 19 and 24A). In

contrast, under the corresponding reaction conditions, other reagents only generated the

difluoromethylene phosphonium ylide (Fig. 24B and C). Therefore, Ph3P+CF2CO2− holds

unique status as a reagent that can generate reactive species for both difluoroolefination or

difluorocyclopropanation reactions.

The reactive :CF2 intermediate has also undergone cycloadditions with alkynes to access

strained difluorocyclopropenes. Using this strategy, a number of difluorocyclopropenyl

steroids were synthesized (Fig. 25A) [63]. Difluorocylopropenes were also used as

precursors to biologically active compounds that showed potent insecticidal activities (Fig.

25B) [64]. Using the same strategy, a simple and efficient method for the preparation of 3,3-

difluoroiodocyclopropenes provided access to interesting fluorinated building blocks [65].

In this case, the combination of TDFA and NaF (10 mol%) generated :CF2, which

subsequently reacted with the alkynyl iodide. These new iodides were further functionalized

by: 1) Heck type cross-coupling reactions with α,β-unsaturated compounds; 2)

trifluoromethylation using CuI and TFDA; 3) hydrolysis under acidic conditions to provide

ring opened β-alkyl-β-iodoacrylic acids with exclusive Z-configuration (Fig. 25C).

2.6 Heteroatom Difluoromethylation

Reactive :CF2 intermediates, generated from NaO2CCF2Cl, have also inserted into

heteroatom–H bonds to provide difluoromethylated ethers and amines. At only 95 °C,

NaO2CCF2Cl decarboxylated in the absence of any transition metal catalyst to afford :CF2,

which was directly trapped with a variety of aromatic and heteroaromatic thiols [66].

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Further, the difluoromethylation of nitrogenous heterocycles and phenylselenol were also

successful (Fig. 26).

3) Fluorination and Trifluoromethylation of Substrates that Undergo

Decarboxylation

3.1 Decarboxylation of Acrylic Acid Derivatives

In the preceding section, trifluoromethylation and difluoromethylenation reactions were

realized by decarboxylation of fluorine-based reagents to generate CF3−, :CF2 or F2C=PR3.

Contrary to this strategy, fluoroalkylation and fluorination can also involve decarboxylation

of the substrate in the presence of fluoroalkylating or fluorinating reagents. This developing

strategy already provides medicinal chemists facile access fluoroalkyl-substituted alkenes,

α-trifluoromethyl ketones, alkyl fluorides, and [18F]-labeled di- and tri-fluoromethylated

arenes directly from a vast number of carboxylic acids that already exist in pharmaceutically

important building blocks [67–75].

A series of Cu-mediated decarboxylative fluoroalkylation reactions were developed that

converted α,β-unsaturated [67], β,γ-unsaturated [68], and propargylic [69] carboxylic acids

to fluorinated species using Togni-type electrophilic fluoroalkylating reagents (Fig. 27) [76–

77]. Using the combination of catalytic CuF2 and IIII–CF3 reagents, a variety of α,β-

unsaturated acids were stereoselectively converted to E-vinyl trifluoromethanes [67] (Fig.

27A). Similarly, E-vinyl difluoromethylsulfones could be accessed using a DMEDA–CuII

catalyst system, and an IIII–CF2SO2Ph reagent (Fig. 27B). Allylic difluoromethylsulfones

could also be formed in regioselective fashion from β,γ-unsaturated carboxylic acids (Fig.

27C) [68]. Representative difluoromethylsulfone products could be subjected to reducing

conditions and converted to allylic difluoromethanes, which are difficult to selectively

access using other methods. Finally, propargylic alcohols were converted to

trifluoroethylketones using stoichiometric Cu(OAc)2, DMEDA, and a Togni

trifluoromethylating reagent (Fig. 27D) [69]. This unique result, in which an oxygen atom

originating from water was incorporated into the product, was rationalized by considering

inherent differences in substrate reactivity in the context of the proposed mechanisms.

While the mechanisms of the above decarboxylative fluoroalkylation reactions might share

similar intermediates, distinct properties of the substrates provided discrete products.

According to the proposed mechanisms for both substrates, CuII served as a Lewis acid, and

facilitated the reaction by; 1) increasing the electrophilicity of the Togni-type reagents; 2)

promoting decarboxylation; 3) coordinating substrates and reagents to bring reactive centers

into close proximity. The following mechanism was proposed for the decarboxylative

difluoromethylsulfonylation of α,β-unsaturated acids (Fig. 27E) [67]. DMEDA–CuF2

underwent ligand exchange to form a highly electrophilic species I. Another ligand

exchange would form ternary complex II, thus placing the π–system of the alkene in close

proximity to the iodonium group. Nucleophilic attack by the alkene would generate

carbocationic intermediate III, which could decarboxylate to form vinyl–IIII species IV.

Reductive eliminate would provide product, and a series of ligand exchanges would

regenerate the DMEDA–CuF2 catalyst. When propargylic carboxylic acids were used as

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

substrates, the initial steps of the proposed mechanism would be identical, and intermediate

VI would form (analogous to II) [69]. The more difficult nucleophilic attack of the alkyne in

VI towards the iodonium could alter the mechanism (Fig. 27F). In one case, attack of the

iodonium by π–electrons of the alkyne would provide a high-energy vinyl cation (Path 1).

This species could be quenched with water to form intermediate VII, which would

eventually provide product. An alternate mechanism involved the iodonium acting as a π–

acid to activate the alkyne for nucleophilic attack by H2O (Path 2). Intermediate VII would

then undergo subsequent tautomerization, decarboxylation, and reductive elimination to

form the trifluoroethylketone product [69].

Several complementary decarboxylative methods for the construction of E-configured

Cvinyl–CF3 and Cvinyl–CF2 bonds via radical addition–elimination processes were recently

developed [70–71]. A variety of (heteroaryl)cinnamic acids were converted to vinyl

trifluoromethanes using catalytic CuSO4·5H2O, stoichiometric TBHP, and NaSO2CF3 as a

source of ·CF3 (Fig. 28A). An alternative procedure enabled the conversion of electron-rich

cinnamic acids to difluoromethanes using Fe-catalysis with (CF2HSO2)2Zn (DFMS) as a

source of ·CF2H. While both of these methods utilized mild reaction conditions, the

substrate scope was limited to (heteroaryl)cinnamic acids. Alkyl-substituted acrylic acids

failed to give the desired products, which might arise from the instability of a radical

intermediate. Subsequently, a similar strategy was applied to the FeCl3-mediated

decarboxylative trifluoromethylation of α,β-unsaturated carboxylic acids [71]. A variety of

(heteroaryl)cinnamic acids were compatible with the reaction conditions (Fig. 28B). More

importantly, the reaction could be conducted under an open atmosphere. Decarboxylative

trifluoromethylation of α,β-unsaturated carboxylic acids was also accomplished by

photoredox catalysis [72]. fac-Ir(ppy)3 served as a photocatalyst and generated CF3 from

Togni reagent. The mild reaction conditions provided excellent functional group

compatibility, and moderate to high yields of products were obtained (Fig. 28C).

3.2 Decarboxylation of Aromatic and Aliphatic Acid Derivatives

Recently, the selective fluorination of organic compounds via a radical mechanism was

successfully achieved [73]. In this reaction, decomposition of diacylperoxies or tert-

butylperoxiacids generated organic radicals, which reacted with N-

fluorobenzenesulfonimide (NFSI) to afford alkyl fluorides. This procedure demonstrated

that alkyl radicals could undergo fluorine atom transfer to from alkyl fluorides. A broad

range of alkyl radicals, including primary, secondary, tertiary, benzylic, and heteroatom-

stabilized radicals underwent fluorination. In some cases, the products of the reactions

would have been difficult to access using electrophilic or nucleophilic fluorination

procedures.

Ag-catalyzed decarboxylative fluorinations of carboxylic acids have recently been

developed [74–75]. Aliphatic carboxylic acids were converted to the corresponding alkyl

fluorides using AgNO3 and Selectfluor® in aqueous acetone [74]. A catalytic cycle invoking

AgI, AgII, and AgIII was proposed (Fig. 30A). The mechanism initiated with the reaction of

AgI and Selectfluor® to provide AgIII–F. Single electron transfer then generated AgII–F and

a carboxyl radical, which decarboxylated to form the corresponding alkyl radical. Reaction

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

of AgII–F with the organic radical then provided the fluorinated product [74]. Under similar

reaction conditions, di- and trifluoromethylated arenes were synthesized from readily

available α, α-difluoro- and α-fluoroarylacetic acids (Fig. 30B) [75]. Adaptation of this

system to the usage of [18F]Selectfluor bis(triflate) provided access to 18F-radiolabeled

products. Compared to the usage of [18F]F2, the AgNO3/[18F]Selectfluor bis(triflate) system

offered an expanded scope of substrates and in several examples, provided higher

radiochemical yields.

CONCLUSION

Methods for the synthesis of fluorinated organic compounds are important for medicinal

chemistry as they enable the facile construction of biologically interesting molecules. In

recent years, new methods for the installation of fluorine-containing functional groups have

been developed that utilize powerful strategies, including decarboxylative coupling. As the

field of synthetic organofluorine chemistry continues to advance, decarboxylative coupling

should play an important role in the development of more general, functional-group tolerant,

and practical synthetic methods for the synthesis of fluorinated compounds.

Acknowledgments

We thank the donors of the Herman Frasch Foundation for Chemical Research (701-HF12) and the AmericanChemical Society Petroleum Research Fund (52073-DNI1) for financial support, and the NIGMS Training Grant onDynamic Aspects of Chemical Biology (T32 GM08545) for a graduate traineeship (B. R. A.). Further financialassistance from the University of Kansas Office of the Provost, Department of Medicinal Chemistry, and GeneralResearch Fund (2302264) is gratefully acknowledged.

LIST OF ABBREVIATIONS

AIBN Azobisisobutyronitrile

DCE 1,2-Dichloroethane

DCM Dichloromethane

DIPEA N,N-Diisopropylethylamine

DMAc Dimethylacetamide

DMEDA N N’-Dimethylethylenediamine

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

NFSI N-Fluorobenzenesulfonimide

NMP N-Methyl-2-pyrrolidone

MDFA Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate

TBHP tert-Butyl hydroperoxide

TFA Trifluoroacetic acid

TFDA Trimethylsilyl fluorosulfonyldifluoroacetate

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

TMEDA N,N,N’,N’-Tetramethylethylenediamine

Selectfluor 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane

bis(tetrafluoroborate)

References

1. Bégué, JP.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine. John Wiley &Sons; Hoboken: 2008.

2. Ojima, I., editor. Fluorine in Medicinal Chemistry and Chemical Biology. Blackwell Publishing Ltd;West Sussex: 2009.

3. Liang T, Neumann CN, Ritter T. Introduction of fluorine and fluorine-containing functional groups.Angew Chem Int Ed. 2013; 52:8214–8264.

4. Liu G. Transition metal-catalyzed fluorination of multi carbon–carbon bonds: new strategies forfluorinated heterocycles. Org Biomol Chem. 2012; 10:6243–6248. [PubMed: 22733139]

5. Hollingworth C, Gouverneur V. Transition metal catalysis and nucleophilic fluorination. ChemCommun. 2012; 48:2929–2942.

6. Tomashenko OA, Grushin VV. Aromatic trifluoromethylation with metal complexes. Chem Rev.2011; 111:4475–4521. [PubMed: 21456523]

7. Bryan MC, Dillon B, Hamann LG, Hughes GJ, Kopach ME, Peterson EA, Pourashraf M, Raheem I,Richardson P, Richter D, Sneddon HF. Sustainable practices in medicinal chemistry: current stateand future directions. J Med Chem. 2013; 56:6007–6021. [PubMed: 23586692]

8. Rodríguez N, Goossen LJ. Decarboxylative coupling reactions: a modern strategy for C–C-bondformation. Chem Soc Rev. 2011; 40:5030–5048. [PubMed: 21792454]

9. Weaver JD, Recio A, Grenning AJ, Tunge JA. Transition metal-catalyzed decarboxylative allylationand benzylation reactions. Chem Rev. 2011; 111:1846–1913. [PubMed: 21235271]

10. Lifongo LL, Bowden DJ, Brimblecombe P. Thermal degradation of haloacetic acids in water. Int JPhys Sci. 2010; 5:738–747.

11. Carr GE, Chambers RD, Holmes TF, Parker DG. Sodium perfluoroalkane carboxylates as sourcesof perfluoroalkyl groups. J Chem Soc Perkin Trans I. 1988:921–926.

12. Chang Y, Cai C. Trifluoromethylation of carbonyl compounds with sodium trifluoroacetate. JFluorine Chem. 2005; 126:937–940.

13. McReynolds KA, Lewis RS, Ackerman LKG, Dubinina GG, Brennessel WW, Vicic DA.Decarboxylative trifluoromethylation of aryl halides using well-defined copper-trifluoroacetateand –chlorodifluoroacetate precursors. J Fluorine Chem. 2010; 131:1108–1112.

14. Duan JX, Chen QY. Novel synthesis of 2,2,2-trifluoroethyl compounds from homoallylic alcohols:a copper(I) iodide-initiated trifluoromethyl-dehydroxylation process. J Chem Soc Chem Commun.1994:725–730.

15. Tan L, Chen C-y, Larsen RD, Verhoeven TR, Reider PJ. An efficient asymmetric synthesis of apotent COX-2 inhibitor L-784,512. Tetrahedron Lett. 1998; 39:3961–3964.

16. Ambler BR, Altman RA. Copper-catalyzed decarboxylative trifluoromethylation of allylicbromodifluoroacetates. Org Lett. 2013; 15:5578–5581. [PubMed: 24117395]

17. Larsson JM, Pathipati SR, Szabó KJ. Regio and stereoselective allylic trifluoromethylation andfluorination using CuCF3 and CuF reagents. J Org Chem. 2013; 78:7330–7336. [PubMed:23786623]

18. Miyake Y, Ota S-i, Nishibayashi Y. Copper-catalyzed nucleophilic trifluoromethylation of allylichalides: a simple approach to allylic trifluoromethylation. Chem Eur J. 2012; 18:13255–13258.[PubMed: 22965685]

19. Chen QY, Wu SW. Methyl fluorosulfonyldifluoroacetate: a new trifluoromethylating agent. JChem Soc Chem Commun. 1989:705–706.

20. Chen QY, Yang GY, Wu SW. Copper electron-transfer induced trifluoromethylation with methylfluorosulfonyldifluoroacetate. J Fluorine Chem. 1991; 55:291–298.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

21. MacNeil JG, Burton DJ. Generation of trifluoromethyl copper from chlorodifluoroacetate. JFluorine Chem. 1991; 55:225–227.

22. Su D-B, Duan J-X, Chen Q-Y. Methyl chlorodifluoroaceate: a convenient trifluoromethylatingagent. Tetrahedron Lett. 1991; 32:7689–7690.

23. Duan J-X, Su D-B, Wu J-P, Chen QY. Synthesis of trifluoromethyl aryl derivatives viadifluorocarbene precursors and nitro-substituted aryl chlorides. J Fluorine Chem. 1994; 66:167–169.

24. Duan J, Su D-B, Chen Q-Y. Trifluoromethylation of organic halides with methylhalodifluoroaceates—a process via difluorocarbene and trifluoromethide intermediates. J FluorineChem. 1993; 61:279–284.

25. Chen QY, Duan JX. Methyl 3-oxo-ω-fluorosulfonylperfluoropentanoate: a versatiletrifluoromethylating agent for organic halides. J Chem Soc Chem Commun. 1993:1389–1391.

26. Long Z-Y, Duan J-X, Lin Y-B, Guo C-Y, Chen Q-Y. Potassium 3-oxo-ω-fluorosulfonylperfluoropentanoate (FO2SCF2CF2OCF2CO2K), a low-temperaturetrifluoromethylating agent for organic halides: it’s α-carbon–oxygen bond fragmentation. JFluorine Chem. 1996; 78:177–181.

27. Chen QY. Trifluoromethylation of organic halides with difluorocarbene precursors. J FluorineChem. 1995; 72:241–246.

28. Roy S, Gregg BT, Gribble GW, Le V-D, Roy S. Trifluoromethylation of aryl heteroaryl halides.Tetrahedron. 2011; 67:2161–2195.

29. Nomura, S.; Kawanishi, E.; Ueta, K. Preparation of glycosides as antidiabetic agents and havinginhibitory activity against sodium-dependent transporter. U.S. Patent Appl Publ US 2012/0258913.2012.

30. Mulder JA, Frutos RP, Patel ND, Qu B, Sun X, Tampone TG, Gao J, Sarvestani M, Eriksson MC,Haddad N, Shen S, Song JJ, Senanayake CH. Development of a safe and economical synthesis ofmethyl 6-chloro-5-(trifluoromethyl)nicotinate: trifluoromethylation on kilogram scale. Org ProcessRes Dev. 2013; 17:940–945.

31. Beletskaya IP, Cheprakov AV. Copper in cross-coupling reactions: the post-Ullmann chemistry.Coord Chem Rev. 2004; 248:2337–2364.

32. Huiban M, Tredwell M, Mitzuta S, Wan Z, Zhang X, Collier TL, Gouverneur V, Passchier J. Abroadly applicable [18F] trifluoromethylation of aryl and heteroaryl iodides for PET imaging.Nature Chem. 2013; 6:941–944. [PubMed: 24153372]

33. Cole EL, Stewart MN, Kittich R, Hoareau R, Scott PJH. Radiosyntheses using Fluorine-18: the Artand Science of Late Stage Fluorination. Curr Top Med Chem. 2014 In Press.

34. Langlois BR, Roeques N. Nucleophilic trifluoromethylation of aryl halides with methyltrifluoroacetates. J Fluorine Chem. 2007; 128:1318–1325.

35. Schareina T, Wu X-F, Zapf A, Cotté A, Gotta M, Beller M. Towards a practical and efficientcopper-catalyzed trifluoromethylation of aryl halides. Top Catal. 2012; 55:426–431.

36. Matsui K, Tobita E, Ando M, Kondo K. A convenient trifluoromethylation of aromatic halideswith sodium trifluoroacetate. Chem Lett. 1981:1719–1720.

37. Li Y, Chen T, Wang H, Zhang R, Jin K, Wang X, Duan C. A ligand-free copper-catalyzeddecarboxylative trifluoromethylation of aryl iodides with sodium trifluoroacetate using Ag2O aspromoter. Syntlett. 2011:1713–1716.

38. Bernstein, P.; Dantzman, C.; Palmer, W. Aryl glycinamide derivatives and their use as NK1antagonists and serotonin reuptake inhibitors. PCT Int Appl. WO 2005/100325. 2005.

39. Austin NE, Avenell KY, Boyfield I, Branch CL, Hadley MS, Jeffrey P, Johnson CN, MacdonaldGJ, Nash DJ, Riley GJ, Smith AB, Stemp G, Thewlis KM, Vong AKK, Wood MD. Design andsynthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamineD3 receptor. Bioorg Med Chem Lett. 2001; 11:685–688. [PubMed: 11266169]

40. Amii H, Nagaki A, Yoshida J-i. Flow microreactor synthesis in organo-fluorine chemistry.Beilstein J Org Chem. 2013; 9:2793–2802. [PubMed: 24367443]

41. Chen M, Buchwald SL. Rapid and efficient trifluoromethylation of aromatic and heteroaromaticcompounds using potassium trifluoroacetates enabled by a flow system. Angew Chem Int Ed.2013; 52:11628–11631.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

42. McReynolds KA, Lewis RS, Ackerman KG, Dubinina GG, Brennessel WW, Vicic DA.Decarboxylative trifluoromethylation of aryl halides using well-defined copper-trifluoroacetateand -chlorodifluoroacetate precursors. J Fluorine Chem. 2010; 131:1108–1112.

43. Fuqua SA, Duncan WG, Silverstein RM. A one-step synthesis of 1,1-difluoroolefins fromaldehydes by a modified Wittig synthesis. Tetrahedron Lett. 1964; 5:1461–1463.

44. Fuqua SA, Duncan WG, Silverstein RM. A one-step synthesis of 1,1-difluoro olefins fromaldehydes. J Org Chem. 1965; 30:1027–1029.

45. Herkes FE, Burton DJ. Fluoro olefins. I. synthesis of β-substituted perfluoro olefins. J Org Chem.1967; 32:1311–1318.

46. Burton DJ, Herkes FE. A one-step synthesis of β-phenyl substituted perfluoroolefins. TetrahedronLett. 1965:1883–1887.

47. Fuqua SA, Duncan WG, Silverstein RM. A one-step synthesis of 1,1-difluoroolefins from ketones.Tetrahedron Lett. 1965:521–524.

48. Fuqua SA, Duncan WG, Silverstein RM. Synthesis of 1,1-difluoro olefins. II. reactions of ketoneswith tributylphosphine and sodium chlorodifluoroacetate. J Org Chem. 1965; 30:2543–2545.

49. Burton DJ, Herkes FE, Klabunde KJ. The reaction of trifluoromethyl ketones andtrialkylphosphines. J Am Chem Soc. 1966; 88:5042–5043.

50. Zheng J, Cai J, Lin J-H, Guo Y, Xiao J-C. Synthesis and decarboxylative Wittig reaction ofdifluoromethylene phosphobetaine. Chem Commun. 2013; 49:7513–7515.

51. Birchall JM, Cross GE, Haszeldine RN. Difluorocarbene. Proc Chem Soc. 1960; 81

52. Knox LH, Velarde E, Berger S, Cuadriello D, Landis PW, Cross AD. Steroids. CCXXVII.steroidal dihalocyclopropanes. J Am Chem Soc. 1963; 85:1851–1858.

53. Beard C, Dyson NH, Fried JH. The methylenation of unsaturated ketones. Part 1. addition ofdifluoromethylene of enones. Tetrahedron Lett. 1966; 28:3281–3286.

54. Csuk R, Eversmann L. Synthesis of difluorocyclopropyl carbocyclic homo-nucleosides.Tetrahedron. 1998; 54:6445–6456.

55. Fujioka Y, Amii H. Boron-substituted difluorocyclopropanes: new building blocks of gem-difluorocyclopropanes. Org Lett. 2008; 10:769–772. [PubMed: 18225908]

56. Kubyshkin VS, Mykhailiuk PK, Afonin S, Ulrich AS, Komarov IV. Incorporation of cis- andtrans-4,5-difluoromethanoprolines into polypeptides. Org Lett. 2012; 14:5254–5257. [PubMed:23020292]

57. Oshiro K, Morimoto Y, Amii H. Sodium bromodifluoroacetate: a difluorocarbene source for thesynthesis of gem-difluorocyclopropanes. Synthesis. 2010; 12:2080–2084.

58. Tian F, Kruger V, Bautista O, Duan J-X, Li A-R, Dolbier WR Jr, Chen Q-Y. A novel and highlyefficient synthesis of gem-difluorocyclopropanes. Org Lett. 2000; 2:563–564. [PubMed:10814377]

59. Dolbier WR Jr, Tian F, Duan J-X, Li A-R, Ait-Mohand S, Bautista O, Buathong S, Baker JM,Crawford J, Anselme P, Cai XH, Modzelewska A, Koroniak H, Battiste MA, Chen Q-Y.Trimethylsilyl fluorosulfonyldifluoroacetate (TFDA): a new, highly efficient difluorocarbenereagent. J Fluorine Chem. 2004; 125:459–469.

60. Eusterwiemann S, Martinez H, Dolbier WR Jr. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, adifluorocarbene reagent with reactivity comparable to that of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA). J Org Chem. 2012; 77:5461–5464. [PubMed: 22612642]

61. Chang Y, Cai C. Sodium trifluoroacetate: an efficient difluorocarbene precursor for alkenes. ChemLett. 2005; 34:1440–1441.

62. Zheng J, Lin J-H, Cai J, Xiao J-C. Conversion between difluorocarbene and difluoromethyleneylide. Chem Eur J. 2013; 19:15261–15266. [PubMed: 24114936]

63. Crabbe P, Carpio H, Velarde E, Fried JH. Chemistry of difluorocyclopropenes. application to thesynthesis of steroidal allenes. J Org Chem. 1973; 38:1478–1483.

64. Bebia D, Pilorge F, Delbarre LM, Demoute JP. From difluorocyclopropene todifluorocyclopropylidene. Tetrahedron. 1995; 51:9603–9610.

65. Xu W, Chen Q-Y. 3,3-Difluoro-1-iodocyclopropenes: a simple synthesis and their reactions. J OrgChem. 2002; 67:9421–9427. [PubMed: 12492348]

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

66. Mehta VP, Greaney MF. S-, N-, and Se-Difluoromethylation using sodium chlorodifluoroacetate.Org Lett. 2013; 15:5036–5039. [PubMed: 24059700]

67. He Z, Luo T, Hu M, Cao Y, Hu J. Copper-catalyzed di- and trifluoromethylation of α,β-unsaturated carboxylic acids: a protocol for vinylic fluoroalkylations. Angew Chem Int Ed. 2012;51:3944–3947.

68. He Z, Hu M, Luo T, Li L, Hu J. Copper-catalyzed difluoromethylation of β,γ-unsaturatedcarboxylic acids: an efficient allylic difluoromethylation. Angew Chem Int Ed. 2012; 51:11545–11547.

69. He Z, Zhang R, Hu M, Li L, Ni C, Hu J. Copper-mediated trifluoromethylation of propiolic acids:facile synthesis of α-trifluoromethyl ketones. Chem Sci. 2013; 4:3478–3483.

70. Li Z, Cui Z, Liu Z-Q. Copper- and Iron-catalyzed decarboxylative tri- and difluoromethylation ofα,β-unsaturated carboxylic acids with CF3SO2Na and (CF2HSO2)2Zn via a radical process. OrgLett. 2013; 15:406–409. [PubMed: 23305217]

71. Patra T, Deb A, Manna S, Sharma U, Maiti D. Iron-mediated decarboxylative trifluoromethylationof α,β-unsaturated carboxylic acids with trifluoromethanesulfinate. Eur J Org Chem. 2013:5247–5250.

72. Xu P, Abdukader A, Hu K, Cheng Y, Zhu C. Room temperature decarboxylativetrifluoromethylation of α,β-unsaturated carboxylic acids by photoredox catalysis. Chem Commun.201310.1039/C3CC48598F

73. Rueda-Becerril M, Sazepin CC, Leung JCT, Okbinoglu T, Kennephohl P, Paquin J-F, SammisGM. Fluorine transfer to alkyl radicals. J Am Chem Soc. 2012; 134:4026–4029. [PubMed:22320293]

74. Yin F, Wang Z, Li Z, Li C. Silver-catalyzed decarboxylative fluorination of aliphatic carboxylicacids in aqueous solution. J Am Chem Soc. 2012; 134:10401–10404. [PubMed: 22694301]

75. Mizuta S, Stenhagen ISR, O’Duill M, Wolstenhulme J, Kirjavainen AK, Forsback SJ, Tredwell M,Sandford G, Moore PR, Huiban M, Luthra SK, Passchier J, Solin O, Gouverneur V. Catalyticdecarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes. Org Lett. 2013;15:2648–2651. [PubMed: 23687958]

76. Eisenberger P, Gischig S, Togni A. Novel 10-I-3 hypervalent iodine-based compounds forelectrophilic trifluoromethylation. Chem Eur J. 2006; 12:2579–2586. [PubMed: 16402401]

77. Kieltsch I, Eisenberger P, Togni Antonio. Mild electrophilic trifluoromethylation of carbon- andsulfur-centered nucleophiles by a hypervalent iodine(III)-CF3 reagent. Angew Chem Int Ed. 2007;46:754–757.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (1).Reactivity of halodifluoroacetates.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (2).Decarboxylative trifluoromethylation of activated halodifluoroacetates.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (3).Proposed mechanism for CuI-mediated conversion of halodifluoroacetic esters to

trifluoromethanes.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (4).Decarboxylative trifluoromethylation employed in the synthesis of L-784,512.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (5).Cu-catalyzed decarboxylative trifluoromethylation.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (6).Trifluoromethylation of aromatic halides.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (7).Recent developments in decarboxylative aromatic trifluoromethylation.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (8).The synthesis of 18F-labelled trifluoromethylated arenes.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (9).The stoichiometric and catalytic decarboxylative trifluoromethylation of aryl halides using

MeO2CCF3.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (10).The stoichiometric (A) and catalytic (B) decarboxylative trifluoromethylation of aryl halides

using NaO2CCF3.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (11).The decarboxylative trifluoromethylation of aryl bromides using KO2CCF3.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (12).The decarboxylative trifluoromethylation of aromatic halides using KO2CCF3 in a flow

reactor.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (13).Decarboxylative trifluoromethylation of aryl halides using well-defined copper complexes.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (14).General strategy of difluoroolefination.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (15).Mechanisms for the formation of l, l-difluoroolefins.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (16).Synthesis of 1,l-difluoroolefins from ketones.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (17).Mechanism for the formation of butylidenecyclohexane.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (18).Olefination of aryl trifluoromethyl ketones with n-trialkylphosphines.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (19).gem-Difluoroolefination of aldehydes and ketones.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (20).Synthesis of difluoronorcarane via :CF2 intermediate.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (21).Addition of :CF2 to conjugated dienes and enones.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (22).Synthesis derivatives of difluorocyclopropanes.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (23).Synthesis of gem-difluorocyclopropanes using TFDA, MeO2CCF2SO2F, and NaO2CCF3 as

sources of :CF2.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (24).Conversion between :CF2 and difluoromethylene ylide.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (25).Synthesis of different difluorocyclopropene derivatives.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (26).Difluoromethylation of thiophenols, nitrogenous heterocycles and phenylselenols.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (27).Difluoromethylation and trifluoromethylation of unsaturated carboxylic acids.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (28).Decarboxylative trifluoromethylation of α,β-unsaturated unsaturated carboxylic acids via

radical processes.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (29).Decarboxyaltive radical fluorination of diacylperxoides and peroxides using N-

fluorobenzenesulfonimide.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Fig. (30).Fluorination of carboxylic acids via radical mechanisms.

Qiao et al.


NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

nih public access medicinally-relevant products curr top ......fluorinated organic compounds have a...

Documents